Project Summary/Abstract The macular pigment carotenoids, lutein, zeaxanthin, and lutein?s metabolite meso-zeaxanthin are uniquely concentrated in the primate foveal region to form the yellow pigment of the macula lutea where they can enhance visual function and protect against the light-induced oxidative damage that has been associated with age-related macular degeneration (AMD) and other disorders of the retina. Diets and supplements enriched in lutein and zeaxanthin are among the most widely prescribed interventions for patients concerned about future visual loss from AMD, and these xanthophyll carotenoids have become standard-of-care for individuals with large drusen or advanced AMD in one eye based on AREDS2 results; however, it is common in the United States for patients and clinicians to integrate nutritional interventions into clinical practice beyond indications established in large, randomized clinical trials such as AREDS2, and carotenoids are no exception. For example, lutein has recently been incorporated into prenatal supplements and infant formulas without any clinical trials at all, based only on the hope that it might promote health and development of the child?s visual system, and nondietary carotenoids such as meso-zeaxanthin are now being promoted as ?next generation AREDS supplements?, again without adequate clinical or basic science studies. The Bernstein laboratory is dedicated to provide mechanistic insights into the biochemistry, physiology, and pharmacology of the macular carotenoids to optimize rational, safe interventions against blinding diseases throughout the lifespan. The key organizing concept that drives the laboratory?s research is that the specific deposition and protective functions of the three macular carotenoids in the human foveal region are mediated by complex, regulated interplay of binding proteins, transporters, and metabolic enzymes. The research group examines this premise using an integrated approach that includes biochemical studies on the enzymology and protein biochemistry of carotenoid transport and metabolism, animal models for carotenoid function in the eye in health and disease using transgenic ?macular pigment mice? genetically engineered to have enhanced carotenoid uptake into the retina relative to wild-type mice, and advanced imaging techniques with particular emphasis on resonance Raman imaging to localize the macular carotenoids at unprecedented spectral and spatial resolution. The results of these studies will advance mechanistic knowledge of their physiological functions at a molecular level, which will enable basic studies that account for their roles in retinal neuroprotection, as well as clinical studies that will lead to rational, scientifically supported decisions about treatments to prevent visual loss throughout a person?s lifetime.